Sickle-cell diseases are a class of genetic disorders caused by a point mutation that leads to a structural abnormality of hemoglobin in red blood cells. When deoxygenated, the abnormal hemoglobin, HbS, polymerizes, resulting in the characteristic sickle shape of the red blood cell. Sickled cells lack the pliability required to traverse small capillaries and have an increased propensity to adhere to endothelial cells of blood vessels. Patients with sickle-cell anemia are homozygous for the sickle-cell gene (SS); other forms of the disease, which may be less severe, occur in patients who have both the sickle-cell gene and a gene for another hemoglobinopathy, such as β-thalassemia or other mutant hemoglobins (e.g., C or D).
An estimated 70,000 Americans have sickle-cell disease, making it the most common simply inherited disorder in the US. The clinical manifestations of sickle-cell disease vary widely among patients, in both affected organ systems and symptom severity. Morbidity and mortality are generally related to vaso-occlusive complications, including pain crises, acute chest syndrome, osteonecrosis, and splenic infarction and consquent infection. Patients also suffer from increased risk of stroke and cerebral hemorrhage.
Currently, sickle-cell disease is treated with hydroxyurea, with analgesics for pain, or, less commonly, by bone marrow transplantation. Hydroxyurea induces production of fetal hemoglobin, which retards sickling, increases the red blood cell volume, and reduces the number of dense and irreversibly sickled cells in the circulation. It does not cure the disease and must be administered continuously throughout the lifetime of the patient. Bone marrow transplantation can cure the disease but may have potentially fatal side effects. It is also difficult to locate a properly matched donor. Clearly, additional therapies are needed.